Females progress more rapidly to cocaine addiction and the sex hormone estrogen is thought to contribute to this process by enhancing the behavioral effects of cocaine. The goal of this project is to understand on a molecular level how estrogen increases behavioral responses to cocaine. The approach outlined in this proposal is to study the function of estrogen receptors and associated signaling molecules in female mice using two behavioral measures related to cocaine addiction, conditioned place preference and sensitization. Estrogen receptors act in the nucleus of cells to regulate gene expression. Two types of nuclear estrogen receptors, ER? and ?, are expressed in brain regions that control behaviors related to cocaine addiction. However, it is currently not known which of these estrogen receptors or their target genes enhances behavioral responses to cocaine. The goal of the first set of experiments is to determine the estrogen receptor type that promotes behavioral responses to cocaine, using specific activators or inhibitory RNAs. The experiments proposed in the second aim will test if a candidate estrogen-regulated gene, Alk, mediates the effect of estrogen in increasing cocaine sensitization and conditioned place preference, by using a small-molecule inhibitor of ALK protein activity. The last set of proposed experiments will examine in detail the molecular mechanisms of regulation of Alk gene expression in neurons by ER? and the associated transcriptional regulatory protein LMO4, by testing binding of these proteins at the Alk promoter in the presence and absence of estrogen. These studies will provide insight into a new molecular pathway in the brain regulated by estrogen that is relevant to behaviors related to cocaine addiction. Moreover, the Alk gene encodes a receptor tyrosine kinase that is amenable to drug development. A greater understanding of estrogen target genes and the molecular mechanisms of their regulation in the brain will lead to better strategies for differentially treating cocaine addiction in women and men.